Dibenzylethylenediamine-penicillin v



DIBENZYLETHYLENED-PENICILLIN V Richard Brunner, Kandl, Tirol, Hans Margreiter, Radfeld,'

Tirol, and Kurt Rierll, Kundl, Tirol, Austria, assignors to American Home Products Corporation, New York, N. Y., a corporation of Delaware No Drawing. Application June 3, 1955 Serial No. 513,162

Claims priority, application Austria June 21, 1954 1 Claim. (Cl. 260-239.!)

The present invention relates to a process for preparing new salts of penicillin with organic bases which salts are difficultly soluble in water and are particularly suited for oral therapy.

It is known to prepare crystalline salts of penicillin G with organic bases, such as p-eminobenzoyldiethylaminoethanol-penicillin G or quinine-penicillin G which can either be used directly in therapy or which, like N-ethylpiperidine-penicillin G or triethylamin-penicillin G constitute intermediate stages in the production of pure alkali or alkali earth salts of penicillin. The preparation of these relatively difficultly water-soluble base salts of penicillin can be effected in accordance with a known method of operation by reacting alkali or alkali earth salts of penicillin with base salts of organic or inorganic acids, for instonce p-aminobenzoyldiethylaminoethanol hydrochloride, in aqueous or aqueous-alcoholic solution. in accordance with another method of operation which can be used also for the preparation of water-soluble base salts of penicillin, the free organic base is allowed to act in anhydrous organic solvents on the penicillin present in the form of free acid. Another known method which leads to base salts of penicillin which are only difficultly soluble or practically water-insoluble consists in reacting base salts of penicillin with certain base salts of organic or inorganic acids, the base of which differs from the base of the base salt of penicillin used; the base salts of penicillin obtained by this method are more difiicultly soluble in the reaction medium than the base salts of penicillin used as starting material.

All previously known penicillins, pencillin salts or base salts of penicillin, due to the high sensitivity to acid of these penicillins, have the disadvantage of having a low stability so that there are great difiiculties involved in their oral administration. An extensive decomposition of the antibiotic is effected by the free acid present in the stomach so that there were required up to the present time in general in order to obtain penicillin contents in the blood which definitely assure a therapeutic action, at least five to six times as much penicillin as had to be used in parenteral administration in order to obtain the same results. Furthermore, the penicillin salts could be taken only on an empty stomach. The use of various alkaline bufier additions in order to neutralize the hydrochloric acid of the stomach was it is true somewhat successful, but the production of an eliective penicillin content in the blood still had inherent in it relatively large factors of uncertainty so that this form of application could not find introduction into general use. Later on, it was believed that the difficulty water-soluble base salts of penicillin G, for instance in p-aminobenzoyldiethylaminoethanol-penicillin G and in dibenzylethylene-diamine-penicillin G were bettersuited for oral therapy. Soon however one was forced to recognize also in this case that more favorable results were not obtainedwith the particularly difiicultly water-soluble base salts of penicillin 6 than with the water-soluble penicillin salts. .These 'ditficultly soluble penicillin salts are also decomposed by the gastric acid Patented data. 21, 1%58 ice in the form of free acids which brought about an advance in this field. These acid-resistant penicillins, administered preferably in the form of tablets, show practically a the same results as injection preparations, the quantity of penicillin used being only about 1 /2 times as great as the quantity of injection penicillin and furthermore administration on an empty stomach no longer being of such great importance.

The acid-resistant penicillins up to the present time could be administered only in solid form for instance as tablets or pills and it was not possible to use them in liquid form, for instance as an aqueous solution or suspension, such as in the form of the fruits syrups and the like which are so popular in pediatrics. An aqueous suspension of the acid-resistant penicillins (pH about 3) is stable only for a very short period of time; even at higher pl-l values tpl-i 5' to 7) at which the acid-resistant peniclllins are already present in the form of water-soluble salts, the stability conditions are just as poor as in the case of solutions of penicillin G salts. Furthermore, it was found in the aqueous administration of solutions of the readily water-soluble alkali salts of acid-resistant penicllnns that while hlgher'concentrations in the blood can be obtained than when using the same dose of alkali penicillin G, the concentration in the blood is nevertheless below the values which are obtained upon the administration of the same quantity of free acids of the acid-resistant penicillins. "the reason for this may well be that while the tree-acid is liberated by the gastric acid also from the alkali salts of the acid-resistant penicillins, it remains for some time in supersaturated solution. in a supersaturated solution, the acid resistant penicillin acids are more stable than the tree acid of penicillin G but less acid-resistant than the crystalline acid-resistant penicillin acids.

1 he ob ect of the present invention is to prepare new diificultly soluble base salts of penicillins which do not experience a decrease in their activity either in neutral or in weakly acid or acid media and with which it is possible to prepare stable aqueous suspensions suitable particularly tor oral therapy.

The method in accordance with the invention for the preparation of new difticultly Water-soluble salts of peniclllln with organic bases consists essentially in reacting acid-resistant penicillins with organic nitrogen bases such as acrldine, diphenylethylamine, benzylphenylethylamine, dibenzyletnylenediamlne or the like, so as to form base penicillins which have a high stability in aqueous suspension and do not experience any substantial decrease of the penicillin activity in an acid medium. Furthermore, the bases dibenzylamine, phenylethylbenZylam-ine and the like can be reacted with the acid stable penicilL'ns forming difiicultly water soluble base penicillins.

By acid-resistant penicillins there is to be understood in the present invention, penicillins which have the general formula C H O NS-NHCO(R X),,R in which R is a bivalent, possibly substituted, aliphatic radical, X is oxygen, sulfur or the NH group, n is a whole number from 1 to 5 and R is an aliphatic, araliphatic and/or aromatic, possibly substituted, radical. penicillins differ typically in their properties from the normal penicillins G, X, F and K. Examples of such acidresistant penicillins are phenoxymethyl-penicillin, p-oxyphenoxymethyl-penicillin, p-nitrophenoxymethyl-penicil lin, phenylmercaptomethyl-penicillin or the like.

In accordance with one particularly suitable embodiment of the invention, the new base salts of penicillin These can be prepared by reacting the free acids of the acidresistane penicillins with the free organic basesin organic solvents such as butylacetate, amylacetate, ether, chloroform; acetone, etc. The acid-resistant penicillins can however also be reacted in the form of their salts, preferably their alkali or alkali earth salts, in aqueous solution,rpossibly with the addition of Water-miscible organic solvents. for instance aliphatic amides such as formamide. acetamide and the like. with salts of organic bases. Furthermore. the difiicultly soluble base salts of the ac dresistant penicillins in accordance with the present invention can be obtained in a good yie d also bv reacting the base salts of acid-resistant penicillins with base salts of organic or inorganic acids. possibly sus ended n solventssthe bases of which are different from the bases of the base salts of the penicillin used and which form base salts which are m re diflicultly soluble in the reaction medium than the base salts of the penicillin which constituted the starting point. The said reactions can be carried out at normal or elevated temperature.

The solubilitv pro erties of the base salts of acid:

resistant penicillins differ in many cases from the solubility properties of the corresponding base salts of penicillin G. Thus for instance the best known hase salt of penicillin G namely p-aminobenzovldiethvl minoethanol-penicillin G. at room temperature has a s lubili v in water of only about 0.5% while p-aminobenzoyldiethylaminoethanol-phenoxvmethyl-oenicillin at the same temperature has a much greater solubility, namely a solubility of about 6%.

it is known from the difficultly wateroluble penicillin G salts that the relativelv more readily water-soluble salts such as novocain-penicillin G are not very stable in aqueous suspensions since the substantial fraction of the salt dissolved in the water decomposes. in which connection a further fraction of the s lid phase passes into solution. etc. Bv reducing the solubi itv of the novocainpenicillin G which can be done for instance by additives having a common ion, such as novocain h drochloride. there are obtained suspensions having a stab lity of about 1 year at room temperature. However, other particularly difiicultly soluble penicillin G salts such as acridinepenicillin G. dibenzyl-ethylenediamine-penicillin G, etc. also give such stable aoueous penicillin sus ensions.

These difiicultly soluble penicillin G salts are decomposed in the stomach by the gastric acid forming the free penicillin G acid and the hydrochlorides of the base, in which connection. as a result of the acid instability of the free penicillin G acid a substantial loss inactivity occurs so that these salts are practicallv iust as unsuitable for oral therapy as the readily soluble alkali penicillin G salts.

In the case of the new base salts of the acid-resistant penicillins of the present invention. there does not occur upon passage through the stomach any loss in activity as noted even though to a far lesser extent than in the case of penicillin G'salts. when using alkali and alkali earth salts of the acid-resistant penicillins. This is probably due to the fact that the solid phase of the base penicillin forms nuclei centers for the crvstallization of the free acids of the acid-resistant penicillins, as a result of which supersaturation is responsible for the decrease in activity of the alkali and alkali earth salts of the acidresistant penicillins in oral therapy is done away with. For the preparation of stable aqueous suspensions there are particularly well-suited base salts, the solubility of which in water is less than 0.2%, a base salt having a water solubility of between 0.03% and 0.1% being particularly advantageous.

Taking into consideration the fact that the milligram activities, due to the fact that the molecular weights generally do not differ very greatly, are about 800 to 1000 units, the saturated aqueous solutions have activities of an order of magnitude of about. 1000 units per cc.

Base salts of acid-resistant penicillins. the solubility properties of which meet the above conditions are for instance acridine phenoxymethyl penicillin, dibenzylethylenediamine phenoxymethyl penicillin, phenylethylbenzylamine phenoxymethyl penicillin. diphenylethylaminephenoxymethyl-penicillin and the like. In the-oral administration of such stable suspensions of difiicultly not unsubstantially greater water solubility than the corresponding salt of penicillin G (0.03% as compared with. 0.01% at room temperature), which results in certain advantages in connection with the parenteral use of this compound. Thus it was possible with dibenzylethylenediamine-penicillin G after a single injection still to detect. penicillin in the blood after many days and in some cases even after 1 to 2 weeks. Long-lasting penicillinconcentrations in the blood are to be sure desirable but on the other hand, such concentrations can also entail substantial risks. Thus. for instance. in certain cases. the resistance of pathogenic germs can be favored thereby. Corresponding to the very low water-solubility of dibenzylethylenediaminc-penicillin G, the blood concentrations even after only I to 2 days have such an order of magnitude that this danger of the production of resistance to pathogenic germs exists. Upon viewing the blood concentration curves obtined in the therapeutic administration of this penicillin G salt, it is seen that starting from the 2nd or 3rd day after the injection, the concentration in the blood is in the region of about 0.06 to 0.12 Oxford units per cc. of serum and that this value under certain circumstances remains at this level for many days. In view of the fact that by the formation of resistant strains, the sensitivity limits in the case of many pathogenic staphylococci and streptococci have been substantially increased, in many countries today a value of 0.] Oxford units per cc. of serum is taken as the lowest limit for a therapeutically active penicillin concentration in the blood. Blood concentrations which lie below the said value or do not substantially exceed it are the more dangerous the longer they appear in the blood plasma. Aside from the dangers inherent in the use of such difiicultly soluble penicillin salts in therapy allergy solubility of this penicillin salt, so that long continuing 7 blood concentrations in the region of 0.06 to 0.12 unit per cc. are avoided.

Dibenzylethylenediamine-phenoxymethyl-penicillin also appears to be a salt which has optimum solubility for.

depot preparations which are tobe administered parenterally, since its solubility is between the solubility of p-' aminobenzoyl-diethylaminoethanol-penicillin G and dibenzylethylenediaminc-penicillin G.

Example I.To a solution of 7.44 grams phenoxymethyl-penicillin sodium of 1600 units per milligram in 200 cc. of water there were added 3.2 grams dibenzylcthylcnediamine hydrochloride which had been dissolved in 200 cc. of water. There was immediately formed a precipitate of dibenzylethylenediamine-phenoxymethylpenicillin which was suction filtered, washed with water and dried. Yield: 9.1 grams dibenzylethylenediaminephenoxymethyl-penicillin of 1160 units per milligram (iodometric test)=87.7% of the theoretical amount.

The substance upon being dried to constant weight had a melting point of 105 to 109 C.; solubility in water was 0.03% at 24 C.

Example 2.To 200 cc. phenxoymethyl-penicillin-containing butylacetate phase at 59,500 units per cc. (iodometric test) there were added 4.22 grams phenylethylbenzylamine base which had been dissolved in 200 cc. butyl acetate. The precipitate of phenylethylbenzylamine-phenoxymethyl-penicillin which formed after standing for several hours was suction filtered and thereupon washed with ether and finally dried. The yieldwas 10.6 grams phenylethylbenzylamine-phenoxymethyl-t penicillin at 1016 units per milligram (iodometric test): 90.5% of the theoretical amount. The solubility in water was 0.09% at 24 C.

Example 3.-1.35 grams quinine-phenoxymethyl-penicillin at 802 units per mg. were suspended in a solution of 0.67 gram 2-ethoxy-6,9-diaminoacridin-lactate (Rivanol) in 30 cc. of water. The suspension was shaken for three hours in a shaking machine at room temperature and thereupon set aside for about 12 hours at a temperature of 4 C. In this way there were obtained 1.12 grams Z-ethoxy-6,9-diaminoacridin-phenoxymethyl-penicillin at 860 units per mg. (iodometric test) which corresponds to a yield of 89.2% of the theoretical amount. The solubility in water was 0.11% at 24 C.

We claim:

As a new compound, the phenoxy-methyl penicillin salt of N,N'-dibenzylethylenediamine.

References Cited in the file of this patent UNITED STATES PATENTS OTHER REFERENCES Brandt et al.: Osten Chem. Ztg., vol. 55, January 1954, page 18.

Abraham et al.: Brit. J. Exptl. Path, vol. 23, June 1942, page 108. 

